In nuclear medicine, various techniques have been used to visualise the presence of a tumour within a body. In quantitative terms, technetium (Tc) compounds are by far the most important radiopharmaceuticals used today with an estimated market share of more than 80%.
For radiomedical purposes, the isotope 99Tc is important not in its slowly β-decaying ground state but in a metastable, nuclear excited state, i.e. as exclusively γ-emitting 99mTc with a diagnostically useful half-life of six hours. One of the major reasons for the popularity of this radioisotope in radiodiagnostics is the availability of an easily operable technetium ‘reactor’ or ‘generator’, which allows the convenient preparation of applicable solutions in a normal clinical environment.
It is known from the prior art to use the pertechnetate anion [99mTcO4]− for medical imaging of thyroid disease, based on the principle that the pertechnetate anion would behave similarly to iodine and be taken up by the thyroid. The pertechnetate anion has also been used to image heart, brain, kidney and liver. However, a growing demand for more specific imaging agents has led to the development of covalently linking an appropriate technetium complex to a small peptide or biologically active molecule (BAM). Examples known from the prior art include: Tcv complexes linked to bisamidedithiol proligands such as ethylenecysteine diester for use in imaging cerebral blood flow in the brain; 99mTc-teboroxime and 99mTcN-NOET for imaging the heart disease; 99mTc-HIDA, 99mTc-Lidofenein, 99mTc-Mebrofenin for imaging the hepatobilary system; 99mTc-diethylenetriaminepentaacetic acid for imaging kidney disease; and 99mTc-complexes of phosphonate ligands for imaging bone disease. However whilst these compounds are tissue specific none of them is specific for tumour detection.
Further developments in the use of 99mTc in medical imaging are based on adapting the outer surface of a technetium complex so as to contain groups necessary for receptor binding. For example, such developments include labelling progesterone receptors with 99mTc to identify breast tumours, labelling central nervous system receptors with 99mTc to identify psychiatric conditions, epilepsy and Alzheimer's disease and labelling a variety of antibodies with 99mTc.
The problem associated with this group of prior art compounds is that, whilst they may be tissue specific, only 99mTc labelled progesterone receptors and 99mTc labelled tumour antibodies can be considered as tumour specific imaging agents. Moreover, these compounds are expensive, laborious and difficult to make and often are quite difficult to handle.
A 99mTc labelled imaging agent that is cell selective, inexpensive and simple to make would offer immediate advantage over the prior art.
In the present invention we have exploited the characteristics of cell behaviour and developed a naturally occurring protein which we have labelled with 99mTc.
Amongst other characteristics/factors, tumour cells can be distinguished from normal cells by their rapid rate of proliferation. A rapid rate of cellular proliferation creates a high energy requirement in tumour cells for most cellular processes, including a high demand on metal transportation into the cell by metal transport proteins.
One such group of metal transport proteins are transferrins which includes lactoferrin and, being naturally occurring proteins within the body with a transport function, transferrins inherently transport across all membranes, including the blood-brain barrier. The mechanism by which transferrins enter the cells and release iron into the cells is as follows. Circulating transferrin is bound to a specific receptor on the cell surface and is subsequently taken up as a receptor/transferrin complex by endosomes into the cytosol. Once the receptor/transferrin complex is in the cytosol the receptor/transferrin complex releases the Fe3+ or “demetallates” and the apotransferrin and receptor are released back out through the cytosol to the cell surface where they may be degraded, or recycled.
We have used the inherent ability of metal transport proteins to target cells combined to develop the imaging agents of the present invention.
Accordingly we believe that the present invention, in one aspect, provides tumour-specific imaging agents which will assist the clinician to make an early clinical diagnosis without the need for invasive exploratory investigation.